Functional analysis of retinoic acid receptor in liver

我们利用白蛋白增强子和启动子建立了在肝细胞中表达视黄酸受体显性阴性形式的转基因小鼠。在3月龄时，转基因小鼠(TG)出现了严重的脂肪性肝炎。脂肪变性的小滴呈微泡状，小叶内散在有灶性坏死灶。肝细胞生长增强，表现为增殖细胞核抗原表达，肝脏呈肿大。除上述改变外，肝细胞异型增生还包括核浆比例增加和染色分布异常。在12个月大的时候，小鼠患上了肝细胞癌。脂肪酸的β氧化在线粒体中受到损害，而在过氧化酶体中则被加速。此外，内质网中脂肪酸的omega氧化增加，导致活性氧物种的产生。这些数据表明，维甲酸对维持肝脏的正常发育是必不可少的，维甲酸可以抑制肝癌的发展。

We developed transgenic mice which express retinoic acid receptor dominant negative form in hepatocytes using albumin enhancer and promoter. At 3 months old, the transgenic mice (Tg) developed severe steatohepatitis. The droplet of steatosis is microvesicular, and the focal necrosis is scattered in the lobule. The growth of hepatocytes was enhanced, indicated by proliferating cell nuclear antigen expression, and the liver showed hepatomegaly. In addition to these changes, liver cell dysplasia including increased nuclear cytoplasmic ratio and abnormal staining distribution. At 12 months old, the mice developed hepatocellular carcinoma. The beta oxidation of fatty acid is impaired in mitochondria, and instead it was accelerated in peroxisome. Furthermore, omega oxidation of fatty acid in the endoplasmic reticulum was increased, resulting in production of reactive oxygen species. These data suggest that retinoic acid is essential for maintain the proper development of liver, and that retinoic acid depresses liver cancer development.